Types and preferred sources of information concerning herbal medicinal products: face‐to‐face interviews with users of herbal medicinal products

Forty per cent of users of herbal medicinal products (HMPs) seek information, mainly concerning side‐effects, how HMPs “work” and their uses, before purchase of HMPs Users of HMPs consult mainly non‐pharmacy, non‐professional sources for information on HMPs Almost 60 per cent of users of HMPs had used conventional medicines and HMPs concurrently in the previous 12 months HMP users' sources of information on HMPs and the apparent extensive use of HMPs concurrently with conventional medicines raise concerns and may have implications for pharmaceutical care     

European legislation on herbal medicines: a look into the future.

Harmonization of the market for herbal medicines is a fundamental requirement for European industries and health professionals and it will also be useful for consumers. Herbal medicines are generally sold as food supplements, but a common regulatory status in the various European countries does not exist. As a consequence, information on clinical indications for use, efficacy and safety are influenced by different opinions, according to the clinical or traditional experience of various folk medicines available in each European country. The European Directive 2004/24/EC released in 2004 by the European Parliament and by the Council of Europe provides the basis for the use of herbal medicines in Europe going forward. The Directive establishes that herbal medicines released in the market need authorization by the national regulatory authorities of each European country and that these products must have a recognized level of safety and efficacy. The safety of herbal medicinal products will be evaluated on the basis of existing scientific literature (data from clinical studies, case reports, pre-clinical studies). When data on safety are not sufficient, it will be communicated to consumers. According to the criteria of safety and efficacy, we will have two kinds of herbal medicinal products in the future: (i) 'well established use herbal medicinal products' (medicinal herbs with a recognized level of safety and efficacy); and (ii) 'traditional use herbal medicinal products'. The later category will include those medicinal herbs that do not have a recognized level of efficacy but are acceptably safe. Even though the fundamental objective of the new European herbal legislation is the harmonization of the market of herbal medicines, important regulations have been introduced, which will contribute to safer use of herbal substances if adopted by the whole of the European community.     

Regulatory Status of Herbal Medicinal Products in Germany

Abstract

Preparation claiming certain indications are regarded as medicinal products in Germany. The German Medicines Law applies uniformly to all medicinal products, including herbal medicinal products. A pre-marketing approval is required including proof of quality, safety, and efficacy. The quality documentation comprises the raw material and its purity, the manufacturing process, the control of the final product and its stability. Pharmacological and toxicological examinations are requested in principle, and efficacy has to be proven by clinical studies. However, for substances with a “well-established medicinal use”, data from published literature may be used to substantiate safety and efficacy. As a national approach to review medicinal products, a system of monographs was established. For herbal medicinal products, Commission E was responsible for the evaluation of more than 300 medicinal plants. Recent European developments, particularly in the field of “well-established medicinal use” and “traditional use”, include harmonized assessment criteria for herbal medicinal products.     

Challenges for Cell-Based Medicinal Products From a Pharmaceutical Product Perspective

Advanced therapy medicinal products (ATMPs), such as somatic cell-therapy medicinal products or tissue-engineered products for human use, offer new and potentially curative opportunities to treat yet untreatable diseases or disorders. For cell-therapy medicinal products (CBMPs), multiple stability and quality challenges exist and relate to the cellular composition and unstable nature of these parenteral preparations. It is the aim of this review to discuss open questions and problems associated with the development, manufacturing and testing of CBMPs from a pharmaceutical drug product perspective. This includes safety, storage and handling, particulates, the choice of container closure systems and integrity. Analytical methods commonly used to evaluate the quality of the final CBMP to ensure patient's safety will be discussed. Particulate contamination in final products deserve special attention since CBMPs cannot be sterile filtered. Visible and sub-visible particles may represent environmental contaminations or may form during storage. They may be introduced from processing materials such as single use product contact materials, ancillary materials, or any components such as primary packaging used for the final product. Currently available analytical methods for detecting particulates may not be easily applicable to CBMPs due to their inherent particulate nature and appearance.     

Current regulatory challenges and approaches in the registration of herbal drugs in Europe

Herbal medicines have formed the basis of healthcare worldwide since the earliest times and are still widely used. Recognition of their clinical, pharmaceutical, and economic value is still growing, although this varies widely between countries. Legislative controls in respect of medicinal plants have not evolved around a structured control model. There are different ways in which countries define medicinal plants or herbs or products derived from them, and countries have adopted various approaches to licensing, dispensing, manufacturing, and trading to ensure their safety, quality, and efficacy. The legal situation regarding herbal preparations varies from country to country. A critical problem in the evaluation of herbal drug products is the fact that they are complex mixtures of constituents and the constituents responsible for the therapeutics effects are unknown, which also complicates the stability of these products. A detailed literature survey of the current regulatory challenges and approaches in the registration of herbal drugs in Europe was performed to identify recently introduced changes in regulations or newly introduced regulations compliant with the regulatory bodies.     

Regulation of medicinal plants for public health - European community monographs on herbal substances

The European legislation on medicinal products also addresses the medicinal use of products originating from plants. The objective of the legislation is to ensure the future existence of such products and to consider particular characteristics when assessing quality, efficacy, and safety. Two categories are defined: i) herbal medicinal products can be granted a marketing authorisation; and ii) traditional herbal medicinal products can be granted a registration based on their longstanding use if they are complying with a set of provisions ensuring their safe use. The Committee on Herbal Medicinal Products (HMPC) was established at the European Medicines Agency (EMA) to provide monographs and list entries on herbal substances and preparations thereof. Meanwhile, approx. 100 monographs have been published, which define a current scientific and regulatory standard for efficacy and safety of herbal substances and herbal preparations used in medicinal products. This harmonised European standard will facilitate the availability and adequate use of traditional herbal medicinal products and herbal medicinal products within the European Union. Consequent labelling shall also enable patients and health care professionals to differentiate medicinal products from other product categories like cosmetics, food supplements, and medical devices.     

Assessment of biotechnology products for therapeutic use

Biotechnology products for therapeutic use include a very diverse range of products, including growth factors, cytokines, hormones, receptors, enzymes, clotting factors, monoclonal antibodies, vaccines, DNA vaccines, gene transfer products, cell therapies and tissue/organ grafts. While some of these products are regulated as medicinal products, the regulatory status of others such as some cell therapies and tissue/organ-based products differs globally and falls within the borderline between the practice of medicine, medical devices and medicinal products. The unclear regulatory status of some products can add to the complexity of the safety assessment of such products. Conventional non-clinical testing paradigms and guidelines for small molecule development are often not relevant for biotechnology products. Guidelines relating to the non-clinical safety evaluation of biotechnology products, gene transfer products and cell therapy products are available and represent a set of general guiding principals to be applied on a case-by-case basis. The quality, safety and efficacy of biotechnology products for therapeutic use are intricately linked, far more so than for conventional medicinal products, leading to the need for increased communication between those responsible for ensuring product quality and those responsible for non-clinical safety testing. Safety issues include microbiological safety (due to the use of biological materials either during the manufacturing process or as an integral part of the products), pharmacological/ biological toxicity (due to excessive primary pharmacology or undesirable secondary pharmacology), immunogenicity and potential tumourigenicity (for example, for growth factors, immunosuppressive monoclonal antibodies and cell therapy products). Genotoxicity and intrinsic chemical toxicity are less of a problem for biotechnology products.     

Regulation of Herbal and Homeopathic Medicines

Currently, national and international regulations for herbal products and homeopathic remedies are subject to extensive review and revision. This is a result of increased consumer demand and a growth in the international marketing of these products. New legislation addresses issues such as concerns regarding product quality, accessibility, depletion of sources of plants leading to extinction, and toxic effects of some medicinal herbs. Evidence-based medicine has increased the need for demonstrable efficacy and safety. Homeopathic products are safe and generally conform to proscribed quality standards but proving therapeutic effectiveness has been controversial. The long-term future for this widely used system of complementary medicine requires more research with positive outcomes. More quality research is required on the efficacy and safety of many herbal health products. Approaches to regulation and licensing of herbal and homeopathic products vary among countries and cultures. There is a need for greater international harmonization and homogeneity. Canada has adopted legislation introducing a Natural Health Products Directorate responsible for a wide range of complementary medicines including herbal and homeopathic products. The objective is to provide ready access to these therapeutic agents while ensuring quality, safety, and efficacy. Products that provide health benefits and resemble food are considered as Functional Foods under food legislation. Regulators in the European Union (EU) are developing legislation to facilitate international trade in herbal and homeopathic products within the Union. Member countries have their own laws, which must be adapted to conform to those of the central parliament. Australia regulates herbal products and homeopathic remedies under the Therapeutic Products Act, 1989, where they are considered as medicines. Homeopathic agents constitute a special section, with modified standards. Countries which accept homeopathic therapy generally acknowledge compendial standards in major national homeopathic pharmacopoeias. This inhibits licensing approval for any new product or delivery system not in the compendia. The US categorizes most herbal products as supplements under the Dietary Supplement Health Education Act of 1994. There is postmarket notification and the US FDA has to demonstrate any problem with safety. The World Health Organization (WHO) is promoting standards for regulating Traditional Medicine, including quality, safety, and efficacy. Important therapeutic systems covered by WHO include those of China, Japan (Kampo) and India (Ayurveda). New regulations for herbal products will enable the consumer to make informed choices based upon improved research data, quality standards, and product labeling.     

Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations

To be effective, herbal medicinal products are expected to meet comparable standards concerning the assessment of efficacy, safety and biopharmaceutical quality as chemically defined synthetic drugs as food supplements. However, these requirements are often not fulfilled, particularly regarding the characterization of biopharmaceutical properties such as in-vitro dissolution and in-vivo bioavailability. With respect to the relevance of biopharmaceutical quality of herbal medicinal products, two different Ginkgo biloba brands (test product: Ginkgo biloba capsules; reference product: Ginkgold) were analysed for dissolution rates and bioavailability of the most relevant active ingredients. Dissolution rates at pH 1 and 4.5 were determined according to the USP 23. The relative bioavailability of ginkgolide A, ginkgolide B and bilobalide was investigated after single oral administration of 120 mg Ginkgo biloba extract as tablets or capsules. Bioavailability data (area under the curve and peak concentration in plasma) were clearly different and did not show bioequivalence of test and reference products. The slow in-vitro dissolution of the test product resulted in a large decrease in bioavailability. These results indicate for the first time that the pharmaceutical properties of a herbal medicinal product have a significant impact on the rate and extent of drug absorption, and very likely on efficacy in humans.     

Unlicensed pharmaceutical preparations for clinical patient care: Ensuring safety

Most medicinal products dispensed to patients have marketing authorization (MA) to ensure high quality of the product, safety, and efficacy. However, in daily practice, to treat patients adequately, there is a medical need for drugs that do not hold MA. To meet this medical need, medicinal products are used in clinical care without MA (unlicensed), such as products prepared by (local) pharmacies: the pharmaceutical preparations. Three types of pharmaceutical preparations are distinguished: (i) reconstitution in excess of summary of product characteristics; (ii) adaptation of a licensed medicinal product (outside its official labeling); (iii) medicinal products from an active pharmaceutical ingredient. Although unlicensed, patients may expect the same quality for these unlicensed pharmaceutical preparations as for the licensed medicinal products. To assure this quality, a proper risk‐benefit assessment and proper documentation in (centralized) patient registries and linking to a national pharmacovigilance database should be in place. Based on a risk assessment matrix, requirements for quality assurance can be determined, which has impact on the level of documentation of a pharmaceutical preparation. In this paper, the approach for good documentation including quality assurance and benefit‐risk assessment will be discussed and possibilities for patient registries are described to make these crucial preparations available for regular patient care. KEY POINTS

• Ensuring pharmaceutical quality and performing a proper benefit‐risk assessment will guarantee safe use of pharmaceutical preparations.
• Good documentation of (ultra‐)orphan treatments can be collected in centralized patient registries and should be combined with existing information in (inter)national databases and self‐reflection of patients.
• Linking patient registries to a centralized database for adverse drug events is highly recommended as it increases safety control of the (ultra) orphan pharmaceutical preparations.

     

Safety assessment of newly marketed herbal medicines--methodological approach (Ginkgo biloba example in Bulgaria)

This study presents a proposal for the methodological approach for postmarketing safety profile assessment based on sales data and information for adverse drug reactions of newly introduced herbal medicinal products in the market. The study covers all herbal medicinal products containing dry extract of Ginkgo biloba leaves allowed for sale in Bulgaria. The methodological approach we create should be used for the establishment of the national herbal drugs policy complying with the recent European regulatory changes and specificity of the therapeutic practice in the country.     

The European Herbal Medicines Directive: could it have saved the lives of Romeo and Juliet?

Herbal medicines have a long tradition of therapeutic use. However, they may occasionally cause dose-related (type A) or idiosyncratic (type B) toxicity and herb-drug interactions are also possible. Toxicity can arise as a result of misidentification or adulteration of the preparation. Legislation (the Directive on traditional herbal medicinal products 2004/24/EC) was enacted on 30 April 2004 to improve public health protection and promote the free movement of traditional medicinal products in the EU. It requires each Member State to set up a simplified registration scheme for manufactured traditional herbal medicines that are suitable for use without medical supervision. Evidence of 30 years of traditional use, at least 15 years of which should normally be within the EU, is required to permit minor claims, replacing the requirement to demonstrate efficacy. Safety is based on evidence in the published literature, although the regulator can also ask for more data if there are safety concerns. The pharmacovigilance requirements and quality standards are the same as for licensed medicines. Patient information is similar to that for any over-the-counter medicine, with an additional requirement for a statement on labels and in advertisements that the indication is based on traditional use. A European positive list of herbal substances will set out the indication, strength, dosing recommendations, route of administration and other information on safe use. Where a product complies with the list, the applicant will not need to demonstrate either the traditional use or the safety of the product. The list will be compiled by the recently established Committee on Herbal Medicinal Products at the European Medicines Agency. EU Member States were required to comply with the Directive by 30 October 2005. Traditional herbal medicinal products already on the market when the Directive became law need not comply with its provisions for 7 years after its coming into force. The public need to be aware that 'natural' does not necessarily mean 'safe' in all circumstances. They should be fully informed about all medicines they take. Consideration also needs to be given to effective regulation of herbal medicines practitioners, so that they are identifiable in law, are governed by professional codes of practice and have agreed standards of training and competency. There are many references to herbal medicines in Shakespeare's tragedy, Romeo and Juliet, which was written around 1595. A herbal medicine (distilled liquor) was almost certainly used to put Juliet into a deep sleep. A poison, possibly of herbal origin, was used by Romeo to take his own life when he thought his beloved Juliet was dead, rather than sleeping. While European herbal medicines regulation seeks to protect the public health by ensuring the necessary guarantees of quality, safety and efficacy, it was poor communication that appears to have triggered the chain of events leading to the death of Romeo and Juliet. Good communication between regulators, practitioners, patients and the public is necessary so that those who choose to take herbal medicines can do so with acceptable safety.     

Cell-Based Therapies Formulations: Unintended components

Cell-based therapy is the fastest growing segment of regenerative medicine, a field that promises to cure diseases not treated by other small molecules or biological drugs. The use of living cells as the active medicinal ingredient present great opportunities to deliver treatment that can trigger the body’s own capacity to regenerate damaged or diseased tissue. Some of the challenges in controlling the quality of the finished cell-therapy product relate to the use of a variety of raw materials including excipients, process aids, and growth promotion factors. The quality of these materials is critical for ensuring the safety and quality of the finished therapeutic products. This review will discuss some of the challenges and opportunities associated with the qualification of excipients as well as that of the ancillary materials used in manufacturing.     

An evaluation of selected herbal reference texts and comparison to published reports of adverse herbal events

OBJECTIVE: There has been a recent proliferation of medical reference texts intended to guide practitioners whose patients use herbal therapies. We systematically assessed six herbal reference texts to evaluate the information they contain on herbal toxicity. METHODS: We selected six major herbal references published from 1996 to 2000 to evaluate the adequacy of their toxicological information in light of published adverse events. To identify herbs most relevant to toxicology, we reviewed herbal-related calls to our regional California Poison Control System, San Francisco division (CPCS-SF) in 1998 and identified the 12 herbs (defined as botanical dietary supplements) most frequently involved in these CPCS-SF referrals. We searched Medline (1966 to 2000) to identify published reports of adverse effects potentially related to these same 12 herbs. We scored each herbal reference text on the basis of information inclusiveness for the target 12 herbs, with a maximal overall score of 3. RESULTS: The herbs, identified on the basis of CPCS-SF call frequency were: St John's wort, ma huang, echinacea, guarana, ginkgo, ginseng, valerian, tea tree oil, goldenseal, arnica, yohimbe and kava kava. The overall herbal reference scores ranged from 2.2 to 0.4 (median 1.1). The Natural Medicines Comprehensive Database received the highest overall score and was the most complete and useful reference source. All of the references, however, lacked sufficient information on management of herbal medicine overdose, and several had incorrect overdose management guidelines that could negatively impact patient care. CONCLUSION: Current herbal reference texts do not contain sufficient information for the assessment and management of adverse health effects of botanical therapies.     

Development of a Chinese herbal medicine toxicology database

BACKGROUND: Use of Chinese herbal medicine has increased steadily in the West and adverse reactions have been reported. However, information is not readily available on the toxicity of the herbs and the management of poisoning. The goals of this project were to retrieve and evaluate scientific evidence on the toxicity of Chinese herbal medicine, to grade the toxicity of individual herbs, and to summarize relevant herb data via a searchable electronic database. METHODS: English and Chinese primary studies were systematically retrieved via journal abstracting databases and key toxicity texts. Partial translation of published research was achieved via an audited process utilizing data extraction forms. Methods for grading herb toxicity (in therapeutic use or overdose) were developed based on a combination of the quality of reports, severity of adverse reaction, supporting animal studies, extrapolation from pharmacology and empirical evidence. RESULTS: Good quality studies on the toxicity of Chinese herbs are lacking. In some cases there is insufficient scientific evidence to create an evidence-based grading of the toxicity of individual herbs. Available data have been summarized into detailed monographs. Twelve herb monographs (with a full toxicity profile and grading) have been completed and summary data for all adequate quality papers used in the grading are linked to the monographs. CONCLUSIONS: The resultant database and monographs represent the first reviews specifically on the toxicity of individual Chinese herbs with toxicological grades based on the evidence of published studies. The database and monographs should assist in promoting the safe and effective use of Chinese herbal medicine.     

Herb–drug interactions: an overview of systematic reviews

OBJECTIVES The aim of this overview of systematic reviews (SRs) is to evaluate critically the evidence regarding interactions between herbal medicinal products (HMPs) and synthetic drugs.METHODS Four electronic databases were searched to identify relevant SRs.RESULTS Forty‐six SRs of 46 different HMPs met our inclusion criteria. The vast majority of SRs were of poor methodological quality. The majority of these HMPs were not associated with severe herb–drug interactions. Serious herb–drug interactions were noted for Hypericum perforatum and Viscum album. The most severe interactions resulted in transplant rejection, delayed emergence from anaesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis and death. Moderately severe interactions were noted for Ginkgo biloba, Panax ginseng, Piper methysticum, Serenoa repens and Camellia sinensis. The most commonly interacting drugs were antiplatelet agents and anticoagulants.CONCLUSION The majority of the HMPs evaluated in SRs were not associated with drug interactions with serious consequences. However, the poor quality and the scarcity of the primary data prevent firm conclusions.     

Herbal hepatotoxicity: a critical review

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements.     

White paper on herbal products. American College of Clinical Pharmacy

Individuals increasingly are taking a more active role in their health care, and herbal products have emerged as a common choice among self-care therapies. Pharmacists are active participants in the care of patients who are taking herbal products. Currently, most pharmacists are not educated adequately about herbal products and other types of alternative medicine. Furthermore, good information about many of these products is not available. These combined factors present a challenge for pharmacists as they seek to provide optimal care and counseling to patients who use herbs or supplements. We recommend the following actions to place pharmacists in better positions as effective agents protecting public safety: Regulations should be implemented at a federal level to require basic levels of standardization and quality control in the manufacture of herbal products. Indexing terms in medical bibliographic systems should be expanded to target herbal products. Funding should be increased for scientific research evaluating herbal products. Pharmacy schools should include a competency statement in their curricula regarding herbal medicines. Continuing education in herbal products should be available and encouraged for all pharmacists. Pharmacists should approach the use of all therapeutic interventions with scientific rigor, whether they are traditional or complementary in nature. Patients will benefit as more information is known and widely disseminated. By actively embracing the responsibility for counseling individuals on the appropriate use of herbal products, pharmacists will become a recognized source of expert information in this rapidly growing area, yielding important improvements in the quality of care.     

“十八反”配伍禁忌研究现状与思考

目的通过查阅、整理相关文献,总结＂十八反＂配伍禁忌的研究现状,探讨十八反毒性作用及物质基础,为临床安全用药提供重要的依据。方法对近15年来国内外发表的相关文献进行分析、整理和归纳。结论 ＂十八反＂不是绝对配伍禁忌,其毒性作用与配伍比例、剂量等诸多因素有关。十八反配伍禁忌合理性仍存在争议,需加强对十八反配伍毒性及毒性成分的深入研究。